Clinical Study Design

BRIAN WASITA, MD., PH.D.

PATHOLOGY ANATOMY DEPARTMENT SEBELAS MARET UNIVERSITY
 Where to Start?

A good clinical study starts with

a good question based on good hypothesis that is
based on good and comprehensive review of the
available evidence from pre-clinical and clinical
data
Type of design depends on the question to be
answered

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What is a research question?

The researcher asks a very specific question and tests a specific hypothesis.
Broad questions are usually broken into smaller, testable hypotheses or
questions.

Often called an objective or aim, though calling it a question tends to help

with focusing the hypothesis and thinking about how to find an answer
 Formulating a Research Question

Focused and specific

What is the prevalence of Hepatitis B surface Antigen in Indonesia ? Cross-sectional study
What are the risk factors for hepatitis B infection? Prospective cohort or case-control
Is interferon a useful therapy for hepatitis B infection? Therapeutic clinical trial
Supported by available data
Is vancomycin better than ceftazidime against gram negative organisms?
Not a replication of already established evidence
Is smoking associated with lung cancer?
Ethical
Answerable
Methods, resources .etc

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 Objectives

Specific aims
Clear and detailed
End point(s)
Primary

The main answer to the research question

Secondary

Answer other related questions

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What makes a poor research question?

a question that matters to nobody, even you

hoping one emerges from routine clinical records

the records will be biased and confounded
theyll lack information you need to answer your question reliably,
because they were collected for another reason

fishing expedition/data dredging gathering new data

and hoping a question will emerge
What makes a good question?

Feasible (answerable with a robust method)

Interesting
Novel
Ethical
Relevant

FINER criteria
Real research questions

Is five days treatment with

injectable ampicillin plus gentamicin
more effective than
chloramphenicol in children under 5
with very severe pneumonia in low
resource settings?

What is the prevalence of HIV

infection in India, and how many
premature deaths does it cause?
How to focus your question

brief literature search for previous evidence

discuss with colleagues

narrow down the question time, place, group

what answer do you expect to find?

Turning a research question into a proposal

who am I collecting information from?

what kinds of information do I need?
how much information will I need? *
how will I use the information?
how will I minimise chance/bias/confounding?
how will I collect the information ethically?

* sample size ask a statistician for help

http://www.bmj.com/collections/statsbk/13.dtl
 Minimising bias and confounding

Chance - measurements are nearly always subject to random

variation. Minimise error by ensuring adequate sample size and
using statistical analysis of the play of chance

Bias - caused by systematic variation/error in selecting patients,

measuring outcomes, analysing data take extra care

Confounding - factors that affect the interpretation of outcomes

eg people who carry matches are more likely to develop lung
cancer, but smoking is the confounding factor so measure likely
confounders too
 Ethical issues the wider aspects

what information to give before seeking consent?

deviation from normal clinical practice?
what full burden will be imposed on participants?
what risks will participants/others be exposed to?
what benefit might participants or others receive?
how might society/future patients benefit in time?
might publication reveal patients identities?
 Exactly what are you planning to do?

PICO

P - who are the patients or whats the problem?

I - what is the intervention or exposure?
C what is the comparison group?
O - what is the outcome or endpoint?
 More on PICO

Patients
disease or condition
stage, severity
demographic characteristics (age, gender, etc.)
Intervention
type of intervention or exposure
dose, duration, timing, route, etc.
Comparison
risk or treatment
placebo or other active treatment
Outcome
frequency, risk, benefit, harm
dichotomous or continuous
type: mortality, morbidity, quality of life, etc.
 Study Design

Your question
Describe
Analyze
Your resources
Retrospective
Prospective
Community
Acceptance of research
Observational

15 Interventional
 Clinical Study Types

Observational Studies
Cohort (Incidence, Longitudinal)
Case-Control
Cross-Sectional (Prevalence)
Case Series
Case Report
Experimental Studies
Uncontrolled Trials
Controlled Trials

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Study designs

Population (P) Outcomes (O)

Interventions (I) or Exposures (E)

Centre for Evidence Based Medicine, Oxford, UK www.cebm.net

 Levels of Evidence
Hierarchy of Strength of Evidence for Treatment Decisions

Level I: N of 1 randomized trial (double-blinded, cross-over)

Level I (A): Systematic reviews of randomized trials
Level I (B): Single randomized trial
Level II (A):Systematic review of observational studies addressing
patient-important outcome
Level II (B):Single observational study addressing important outcome
Level III: Physiologic studies
Level IV: Unsystematic clinical observations (case-reports, anecdotal)

JAMA 2000; 284(10):1290-96

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 Observational study Clinical trial

observational
describe as study
occurring in nature
exposed
outcome
non exposed
allocate
randomly
Ethics!
Clinical
Trial

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 Are you going to observe or experiment?

observational cross sectional, case series, case-control studies,

cohort studies
identify participants
observe and record characteristics
look for associations

experimental before and after studies, comparative trials

(controlled or head to head), randomised trials (ditto)
identify participants
place in common context
intervene
observe/evaluate effects of intervention
 Important issues in Study Design

Validity: Truth
External Validity:
Can the study be generalized to the population
Internal Validity:
Results
will not be due to chance, bias or
confounding factors
Symmetry Principle: Groups are similar

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 Important issues in Study Design

Confounding: distortion of the effect of one risk factor by the presence of

another
Bias: Any effect from design, execution, & interpretation that shifts or influences
results
Confounding bias: failure to account for the effect of one or more variables
that are not distributed equally
Measurement bias: measurement methods differ between groups
Sampling (selection) bias: design and execution errors in sampling

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 Types of observational studies

CROSS - SECTIONAL STUDY

COHORT STUDY

CASE CONTROL STUDY

CASE SERIES/CASE REPORTS

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 Characteristics of observational studies

No control over study units

need to clearly describe study individuals
Can study risk factors that have serious consequences
Study individuals in their natural environment (>>
extrapolation)
Possibility of confounding

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 Aims of observational studies

Evaluate the effect of a suspected

risk factor (exposure) on an outcome
(e.g. disease)
define exposure and disease

Describe the impact of the risk factor

on the frequency of disease in a
population

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Cross - Sectional Study

Exposure and disease measured once, i.e.

at the same point in time

exposed ?
diseased ?
past present future
 Cross - Sectional Study

Random sample from population

i.e. results reflect reference population
Estimates the frequencies of both exposure and outcome in
the population
Measuring both exposure and outcome at one point in time
Typically a survey

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 Cross - Sectional Study

Can study several exposure factors and outcomes

simultaneously
Determines disease prevalence
Helpful in public health administration & planning
Quick
Low cost (e.g. mail survey)
Limitation:
Does not determine causal relationship
Not appropriate if either exposure or outcome is rare
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 Cross-Sectional: Risk Factors for Smoking

Variable OR 95% CI
No. friends who smoke:
- all vs. none of them 36.5 9.3 142.8
- most vs. none of them 18.4 5.5 61.8
- about half vs. none of them 7.5 2.2 26.0
- a few vs. none of them 2.1 0.6 7.9
Any siblings who smoke: Y vs. N 2.8 1.8 4.3
Mother smokes:
Yes vs. No 1.9 1.3 2.9
Have no mother vs No 3.5 0.8 15.030
 Pros and cons of cross sectional study

Examines the relationship between 1) diseases/other health related characteristics and 2) other variables of interest as
they exist in a defined population at one time. Exposure and outcomes both measured at
the same time. Quantifies prevalence, risk, or diagnostic test accuracy
Advantages:
cheap and simple
ethically safe
Disadvantages:
establishes association at most, not causality
recall bias, social desirability bias
researchers (Neyman) bias
group sizes may be unequal
confounders may be unequally distributed
Cross sectional study
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Cohort studies

Follow-up studies; subjects selected on presence or absence of

exposure & absence of disease at one point in time. Disease is
then assessed for all subjects at another point in time.

Typically prospective but can be retrospective, depending on

temporal relationship between study initiation & occurrence of
disease.
 Cohort Study

Individuals selected by exposure status and

future occurrence of disease measured
n n

Exposed yes disease ?

Exposed yes disease ?
no disease ? no disease ?

past present future

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 Pros and cons of cohort study

Data obtained from groups who have already been exposed, or not exposed, to the factor of interest. No allocation of exposure is made

by the researcher. Best for studying effects of risk factors on an outcome.

Advantages:

ethically safe

participants can be matched

can establish timing and directionality of events

eligibility criteria and outcome assessments can be standardised

Disadvantages:

controls may be difficult to identify

exposure may be linked to a hidden confounder

blinding is difficult

for rare disease, large sample sizes or long follow-up necessary

time consuming and expensive

Cohort study
 Prospective Cohort Study

with outcome
Exposed
without
outcome
Cohort
with outcome
Unexposed
without
outcome
Time
Onset
of study Direction of inquiry
37 Q: What will happen?
 Prospective Cohort Study

Appropriate for frequent disease

Can examine only few risk factors
Usually expensive
RR = relative risk = incidence rate ratio
RR : the ratio of the probability of an event occurring (for example, developing a disease,
being injured) in an exposed group to the probability of the event occurring in a
comparison, non-exposed group.
AR = incidence difference

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 41
Case-Control Study

Retrospective
Can use hospital or health register data
First identify cases
Then identify suitable controls
Hardest part: who is suitable ??
Then inquire or retrieve previous exposure
By interview
By databases (e.g. hospital, health insurance)
 Case-Control Study

Diseased and non-diseased individuals are selected first

Then past exposure status is retrieved

exposed ? yes disease

exposed ? no
past present future

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 Case-Control Study Design

Exposed
Cases
Unexposed
Exposed
Controls
Unexposed

Data Time
collection
Direction of inquiry
Q: What happened?
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 Pros and cons of case-control study

Patients with a certain outcome or disease and an appropriate group of controls, without the outcome or
disease, are selected (usually with some matching) then information is obtained on whether the subjects
have been exposed to the factor under investigation.
Advantages:
quick and cheap as fewer people needed than cross-sectional studies
only feasible method for very rare disorders or those with long lag between exposure and outcome
Examines multiple exposures to a single disease
Disadvantages:
reliance on recall or records to determine exposure status
confounders
selection of control groups is difficult
potential bias: recall, selection
 Case Selection
Define source population
Cases
incident/prevalent
diagnostic criteria (sensitivity + specificity)
Controls
selected from same population as cases
select independent of exposure status

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 Control Selection
Random selection from source population
Hospital based controls:
convenient selection
controls from variety of diagnostic groups other
than case diagnosis
avoid selection of diagnoses related to
particular risk factors
limit number of diagnoses in individuals

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Case-control study
Odds Ratio

(OR) is a measure of association between an exposure and an outcome.

The OR represents the odds that an outcome will occur given a particular
exposure, compared to the odds of the outcome occurring in the absence
of that exposure.
Odds ratios are most commonly used in case-control studies,however they
can also be used in cross-sectional and cohort study designs as well
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Case-Control Study
 Summary of Observational Studies

Characteristic Cross - Case Control Cohort

Sectional

Sampling Random sample: Purposive sample: Purposive sample:

population diseased/non- Exposed/non-
diseased exposed
Time One point Retrospective Prospective
Causality Statistical Screening for Testing one (or
association many risk factors few) risk factors
Frequency Prevalence None Incidence
measure
Risk Prevalence (risk) Odds ratio Relative risk, odds
50 parameter ratio, odds ratio ratio
 Incidence vs. Prevalence

Incidence and prevalence are both measures of the extent of disease in a population.
Incidence tells us about a change in status from non-disease to disease, thus being
limited to new cases.
Prevalence includes both new cases and those who contracted the disease in the past
and are still surviving
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Clinical Trials
 Types of Clinical Trials

Treatment trials test experimental treatments, behavioral therapies,

new combinations of drugs, or new approaches to surgery or radiation
therapy

Prevention trials look for better ways to prevent disease in people who
have never had the disease or to prevent a disease from returning
These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle
changes

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 Types of Clinical Trials

Diagnostic trials are conducted to find better tests or procedures for

diagnosing a particular disease or condition

Screening trials test the best way to detect certain diseases or health
conditions

Quality of life trials (also called supportive care trials) explore ways to
improve comfort and the quality of life for individuals with a chronic
illness
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 Clinical Trials Drug Development

Basic Novel In-Vitro In-Vivo

Research Compounds Screening Screening

In Animals
Isolated cells
& tissues

Drug
Clinical Safety
Licensing
Trials I - III Testing
& Release
In Humans

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 Clinical trials in drug development
(Any alternatives)

In-Vitro Tests Can Show Whether:

A compound has the desired effect on isolated cells or
tissues
There are adverse effects on those tissues

In-Vitro Tests Cannot Show Whether:

The desired effect will occur in a complete living system
There will be any adverse effects in a complete living
system

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 Clinical trials in drug development
(Any alternatives)

Animal Tests Can:

Suggest which drugs are likely to be effective in humans
Indicate which drugs may not be harmful in humans
Animal Tests Cannot:
Predict with absolute certainty what will happen in humans

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 Clinical Trials-Phases
Phase I - Does it hurt the Patient?
Usually in normal volunteers, small groups for safety testing
Phase II - Does it help the Patient?
On patients to confirm the effectiveness of the drug
Phase III - Is it any better?
Large groups of patients for statistical confirmation of effect
and incidence of side-effects
Phase IV - Does it work in the community?
Post marketing studies. Fine tuning and new rare findings from a
very large population
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 Phases of Clinical Trials

Phase I trials (a pilot study): Researchers test an experimental drug or treatment in a

small group of people (5-60 subjects) for the first time to
Evaluate its safety
Determine a safe dosage range
Identify side effects

Phase II trials (a larger pilot study): The experimental study drug or treatment is given
to a larger group of people (100 subjects) to see if it is effective and to further
evaluate its safety

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 Phases of Clinical Trials

Phase III trials (RCT): The experimental study drug or treatment is given to large groups
of people (200-3,000 subjects) to
Confirm its effectiveness
Monitor side effects
Compare it to commonly used treatments
Collect information that will allow the experimental drug or treatment to be used safely

Phase IV trials (implementation research):

Post marketing studies
Delineate additional information, including: the drug's risks, benefits, and optimal use

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 Clinical Trial: Study Design

Uncontrolled
Controlled
Before/after (cross-over)
Historical

Concurrent, not randomized

Randomized

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 Experimental Design

Experimental
RCT
Cross-over RCT
Quasi-experimental
Nonrandomized comparison group
Nonrandomized cross-over
Case control (matched or non-matched)
Historical control
One group pre-post design
Cross-sectional (slice in time)
Cohort (repeated measure)
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Nested (one study nested in another)
Quantitative Research

 Randomized Control Design (RCT)

Is the gold standard of all studies

Is prospective

Two or more groups assigned by randomization

Take baseline measure on all groups

Give different treatments

Measure outcome
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 Schemata

Group 1: O1 X1 O2
Group 2: O1 X2 O2
Where O= Observation
Where X= Treatment

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Pros and cons of the RCT

An experimental comparison study where participants are allocated to treatment/intervention or

control/placebo groups using a random mechanism. Best for studying the effect of an intervention.

Advantages:
unbiased distribution of confounders
blinding more likely
randomisation facilitates statistical analysis
Disadvantages:
expensive: time and money
volunteer bias
ethically problematic at times
 Randomized Cross-Over Design

2 groups, each get a different treatment

Washout period

Give each group the other treatment

O1 X1 O2 washout O3 X2 O4
O1 X2 O2 washout O3 X1 O4
Advantage
Can not only compare between groups, but also within groups
Subjects serve as their own controls
Controls for extraneous variables

Not a common design

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 Pros and cons of crossover trial

A controlled trial where each participant has both therapies e.g is randomised to treatment A first then
starts treatment B.

Advantages:
all participants serve as own controls and error variance is reduced, thus reducing sample size needed
all participants receive treatment (at least some of the time)
statistical tests assuming randomisation can be used
blinding can be maintained
Disadvantages:
all participants receive placebo or alternative treatment at some point
washout period lengthy or unknown
cannot be used for treatments with permanent effects
 Non-Randomized Comparison Group

Next best thing to RCT

Used when we cannot randomize our subjects
For example, due to cross-contamination, or facility- or
community-level interventions

Make sure groups are as similar as possible

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 Non-Randomized Cross-Over Design

Same as the previously described randomized cross-over design

But groups are not randomized

O1 X1 O2 washout O3 X2 O4
O1 X2 O2 washout O3 X1 O4

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 Case Control Study

Quick and dirty, but able to obtain lots of information

Used in epidemiology to look at exposures
Retrospective or prospective
Has a comparison group

Sometimes, does not control for extraneous variables

Sometimes, controls for by matching
Sometimes, nested in a larger study (e.g., nested case control)
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 Non-Matched Case Control Example

Worked in Coal Did not work in

Mine Coal Mine
N=20 N=20
Black Lung-Yes 10 0

Black Lung-No 10 20

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 Matched Case Control Examples

Example 1: Want to look at the beta carotene blood levels of the head-
neck cancer patients, smokers compared to non smokers
Match on age, gender, race, BMI, fruit and vegetable intake, cancer
site, cancer stage
Example 2: Want to look at the effect of Doulas on birth outcomes for
pregnant adolescents
Match on age, race, BMI, provider type, gestational age, pregnancy
complications

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 Matched Case Control Example 1

Smoked Not Smoke

N=30 N=30

Beta carotene 50% 50%

High

Beta carotene 50% 50%

Low

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 Historical Controls

Not the best design

Better than no comparison group

Look at a group before an intervention was implemented compared to

after an intervention was implemented
Comparison not at same time

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 Historical Control

Example 1:
Initiation of skin to skin contact following delivery on temperature, breast feeding
rates and blood sugar
Looks at those outcome prior to the intervention and then after this intervention
was initiated
Example 2:
Infections rates in the OR before and after a new protocol implemented
Compare old rates to new rates
O1 O2 O3 O4 X O5 O6 O7
Where O=Observation of infection rate
Where X= New operating room procedures
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 One Group Pre-post Design

O1 X O2

Used a lot in nursing

Not a good design because there is no comparison group

Biggest draw back is it cannot control for historical effect

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 Cross-Sectional Design

Takes a measure of a population at a certain point in time (e.g., a

survey research)
O1

Descriptive
Are easy, fast, and inexpensive
Can determine prevalence of disease
Can look at associations between variables
Cannot determine cause and effect
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 Cohort Study

Tim series, longitudinal, repeated measures

Repeated cross-sectional measures over time
O1 O2 O3

Could have a repeated measures design with a comparison group

Can determine changes in population
Can determine cause and effect
Are expensive and take a long time
Example: Nurses Health Study
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 Nested Design

Cohort Study nested within a repeated measures design

Example: Followed up 600 head-neck cancer patients over time

Did case-control study (n=60) to see if beta carotene blood levels were
different between smokers and nonsmokers

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 Summary

Selection of design should be made on the basis of the particular

hypothesis to be tested with consideration of current state of
knowledge
Consider available resources when deciding on a study design
A clear and organized study design leads to successful results
Observational studies are especially valuable in epidemiology
Clinical trials carry the highest level of evidence and should be pursued
whenever feasible

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Invitro Experiment

Sample : cells, animal blood etc

Group:
Negative control group
Positive control group
Experimental group
Sample size?
Invivo experiment

Sample : animals (rats,mice, dogs,monkeys,zebra fish, etc)

References

1. Hail M. Al-Abdely, Clinical Study: Design and Methods Lecture

2. Huey-Ming Tzeng, Sonia A. Duffy, Lisa Kane Low, Quantitative Research
Lecture
3. Trish Groves, Different types of clinical evidence and study design Lecture